1, 3, 5-triazinyl-phenyl-sulphides carrying a metallic radical



Patented Dec. 25, 1945 UNITED STATES PATENT OFFICE 1,3,5-TRIAZINYL-PHENYL-SULPHIDES CARRYING A METALLIC RADICAL Ernst A. H. Friedheim, New York, N. Y.

No Drawing. Application October 1, 1942, Serial No. 460,413

9 Claims.

This invention relates to therapeutically active, new, asymmetric triazinyl sulphides carrying an organometallic radical, and has particular relation to triazinyl sulphides in which the phenyl group carries an organometallic radical containing Sb, P, Hg or Se atom.

The compounds according to this invention correspond to the general formula fi I 7 CSCaH2(A, B)Me In this formula Cc represents a benzene ring.

X and Y may be equal or different and represent halogen or the residue of any inorganic or organic, aliphatic or cyclic, isocyclic or heterocyclic, monocyclic or polycyclic molecule containing an active hydrogen atom capable of reacting with a cyanuric halide with the formation of hydrogen halide. X and Y, may be f. e. selected from a first group consisting of Cl, Br, I, F, H, OI-I, -Oalkyl, ---O--acyl, NHz, --NHalkyl, Nalkylz, NH-acyl, NH-NHz, NH- NHalkyl, --NalkylNH2, N-alkyl- NIL-alkyl, NH-NHacyl, --N-acyl-NH:,

residues of cyanamide derivatives, residues of substituted guanidines, amino-derivatives of carbohydrates, particularly amino-derivatives of monosaccharides, such as glucose-amine, --SH, substituents of the type S-R wherein R stands for any aliphatic or cyclic groups capable of carrying a SH group, such thioglycolic acid and thiophenoLalkyl radicals and their substitution products, and isocyclic or heterocyclic hydrocarbon radicals, which may be monocyclic or polycyclic, and their substitution products, such as O-aryl groups, substituted-aryl radicals, such as those corresponding to the formula wherein A and B may represent equal Or difierent substituents defined further below, and E may be in ortho-, metaor para-position with respect to the NH or NHNH group and may f. e. represent a radical selected from the group consisting of ---SO3H, SOzNHz, COOH, and metallic radicals, such as SbOsHz, POaHz, SeO3H2, -ASO 3H2, -ASO, V

HG-radica1s. X and/or Y may also stand for substituted sulphur-aryl radicals of the formula or for 1,3,5-triazine groups or residues of triazine derivatives, and said radicals and triazine groups or derivatives maybe linked directly or indirectly to the ring carbon'atomsof the first triazine ring. In the latter case, the link between the above mentioned Saryl-Me radical and the triazine ring carbon may be formed by a cyclic or aliphatic amine radical, f. e. by an -NHaryl, NH-alkyl, NI -I NHaryl, or NI-INH alkyl radical. The link between the first and the substituting triazine ring may be formed by an "NH, 'NIINI-I group or an aliphatic or cyclic v diamine, f. e of the formula NHC NH The radicals A and B may be the same or dif- 0 It has been found that compounds embodying the present invention may be prepared by reacting a triazine derivative carrying at least one sulphhydril group or a tautomeric structure,

with organometallic derivatives or diazobenzene according to the following reaction:

The sulphur containing triazine derivatives used for preparing the compounds according to this invention may be prepared according to known methods by reacting a triazinederivative containing at least one halogen linked to a triazine ring carbon, with alkali sulphide or sulphhydrate. The second and third ring carbon atom in said triazine derivativ may carry identical or different radicals, forexample halogen atoms or NH2 radicals. This method allows for the ready and preparation of a great variety of suitable thiotriazines. In certain cases it may be of advantage to prepare thiotriazine-s by direct ring formation, e. g. by reactions involving the cyan radical, such as dicyanamide, biguanide, thiocyanide.

Compounds embodying this invention may also be prepared from triazine SI-l compounds by reacting them with metal-free diazo-compounds carrying a substituent that can be replaced by a metal radical after the formation of a triazine phenylsulphide.

Furthermore mercury-containing compounds corresponding to this invention may also be prepared by replacing the arsenic radical in triazinethiophenyl-arsenoxide by mercury. The preparation of triazine-thiophenyl-arsenoxide is described in my copending application filed on October 1, 1942.

Example I.26.4 g. of stibanilic acid are dissolved in 100 cc. of a 2N solution of NaOI-I. '7 g. of sodium nitrite are added, and the solution is run in thin stream, with stirring and cooling, into a mixture of 37.5 cc. of HCl (D=1.19) and 250 g. of ice. The reaction mixture is allowed to stand for 30 minutes, and is then run, with rapid stirring into 600 cc. of an aqueous solution containing 17.2 g. of thioammeline and 33.4 g. of anhydrous sodium carbonate. Throughout this step, the temperature of the solution is maintained at about 70 C. Stirring is continued until the reaction mixture fails'to give a color reaction with R-salt, e. g. for 1 hour. The reaction mixture is then boiled for 2 minutes with copper bronze, boneblacked and filtered. The filtrate is acidified with 5N I-ICl, using Congo red as an indicator. During this procedure a precipitate is formed and redissolved in an excess of hydrochloric acid. The acid solution is boneblacked and filtered, and yields on addition of sodium acetate up to a faintly blue coloration, a yellowish precipitate which is filtered off and washed with 20% acetic acid, water and alcohol. This crude diamino-triazine thiophenyl-stibinic acid is redissolved in 15 times its weight of water and the necessary amount of sodium bicarbonate to form a solution slightly alkaline to litmus. The alcaline solution is boneblacked and filtered, and yields on acidification with acetic acid a white precipitate which is filtered off", washed with water and recrystallized out of hot 20% acetic acid. The diamino-triazine-thiophenyl stibinic acid is soluble in aqueous bicarbonate of soda and in an excess of warm, dilute hydrochloric acid. It is insoluble in alcohol and ether. The solution in concentrated warm hydrochloric acid yields 'on cooling a crystalline chlorhydrate. The reaction takes place according to the scheme:

NlH2

lTlHz A trace of the substance fused with metallic sodium gives a deep purple tint on addition of an aqueous solution of nitroprussate.

The same procedure may be followed with a substituted stibanilic acid, such as nitrostibanilic acid and yields the corresponding 'diaminoetriazine-thionitro-stibinic acid.

Diamino-triazine-thiophenyl phosphoric acid may be prepared in a procedure analogous to that hereinbefore described by using instead of stibani lic acid'an equivalent amount of phospham'lic acid or a substituted phosphanilicacid.

Example II .A solution of 240 g. of thiophenyl phosphoric acid (Es-Groom,

prepared by treating diazobenzene phosphoric acid with sodium xanthogenate) in 300 g. of N NaOH is'run, drop by drop, with stirring and cooling into a suspension of cyanuric chloride in 200 cc. of water. Stirring is continued until the reaction mixture shows no color reaction with sodium nitroprussate, e. g. for about 2 hours. On acidification, a white precipitate of dichloro-triazine-thiobenzene-phosphoric acid is formed. The precipitate is filtered off and washed with dilute hydrochloricacid, water and acetone.

The compound is soluble in sodium carbonate solution, and in an excess .of hydrochloric acid. It is insoluble in alcohol and ether. One or both of the halogens of the compound may be substituted by amino groups, by treatment with ammonia.

Example IlI.Following the procedure outlined in Example I, p-diazonitrobenzene isreacted with thioammeline to form diaminotriazine-p-thio-nitrobenzene which is reduced in acetic acid solution with iron to form the diamino-triaz'ine-p--thiophenylamine corresponding to the formula The latter is transformed in acid solution by treatment withsodiumnitrite to the corresponding diazo compound which, on treatment with SbClz is converted into diamino-triazine-p-thiophenylstibinic acid.

The use of substituted diazonitrobenzene in the above procedure allows readily for the-preparation of substituted stibinic acids.

Example IV.35 g. of diamino-triazine-p-thiophenyl arsin oxide corresponding to the formula prepared as described in my copending application filed on October 1, 1942 is dissolved in 300 cc. of n/ 1 NaOH and stirred with 10.8 'g. of mercuric oxide. A clear solution is formed, which, on standing, yields a white precipitate of diaminotriazine-p-thio-phen'yl mercuric acid. The precipitate is filtered oil and recrystallized out of hot acetic acid inform of the corresponding mercury acetate. 1 a I The use of 'diamino-p-thiophenyl arsin oxides, which are substituted in the benzene ring, allows readily for the preparation of correspondingly substituted'mercury compounds.

Example V.-35 g. of p-aminophenyl mercuric acetate are added to '50 ccfof water. 20 cc. of glacial acetic acid are added, and the mixture is heated until a clear solution is obtained. The solution is cooled to 5 C. and diazotized with 7 g. of sodium nitrite dissolved in 30 cc. of water. The orange-brown diazo solution is filtered and run f with rapid stirring into 300 Igvof 2N NaOH .conand containing as X and/or Y active groups f. e.

The substance is a white crystalline powder, solubl in hot acetic acid, and insoluble in cold water and ether.

Example VI.-28.8 g. of meta-aminophenyl selenic acid of the formula V SeOaElz NHz are dissolved in 250 cc. of n/ 1 H01 and diazotized by treatment with 69 g. of NaNOz. The diazo solution is filtered and run with rapid stirring into 250 cc. of 2N NaOH solution containing 14.3 g. of thioammeline, maintained at about 50 C. Upon acidifying the reaction mixture with hydrochloric acid a precipitate is formed, which is filtered off, washed with dilute hydrochloric acid and recrys- :..tallized from hotwater. Th resulting product is a diamino-triazine-m-thiophenyl selenic acid of the formula r r nse V i NHr-O o-s SeOaHg,

Further compounds embodying the present invention, in which X and/or Y stands for a radical other than those described in the above examples,

may be obtained f. e. by first preparing an XY-- triazine compound, in which at least'one carbon atom of the triazine ring carries a halogen, and reacting such triazine compound with a suitable aromatic compound carrying a metallic radical, such as thiophenyl-phosphoric acid. Thiophenyl compounds carrying other Me radicals may be used instead of thiophenyl phosphoric acid. Or th XYtriazinehalogen derivative may be reacted with alkali sulphhydrate in order to form the corresponding.X-Y-thiotriazine, and the latter is reacted with a diazobenzene derivative carrying an Me radical. These reactions between the XY-triazine-halogen compounds or the X-Y-triazineSH compounds and the phen-- ylMe derivatives may be carried out in a manner analogous to that described in the above examples.

Furthermore, triazine derivatives embodying the present invention may also be obtained by reacting a compound corresponding to the general formula halogens or -NH2 groups, with any organic or inorganic compound capable of combining with orreplacing X and/or Y. I -A compound of the formula may be reacted, for example, with thiophenol arsonic acid or arsanilic acid in order to replace one or both Cl-atoms by the corresponding arsonic acid radical.

Compoundsv embodying this invention and carrying A,B substituents other than those described in the above examples, may be obtained with mild oxidizing agents, such as diluted H202 or diluted nitric acid, the -S atom is converted into a'SO- or S0a radical, thus forming a compound corresponding to one of the following formulas:

d-so-ounm, B)Me y .N

and V Th new compounds are adapted to be used as medicinal preparations. They exert a therapeutic action in the infectious diseases, such as those caused by certain protozoa, and certain spirochetes, and have a relatively low toxicity.

. It will be understood that this invention may becarried out in other specific ways than those herein set forth, and the examples should be,

therefore, considered asillustrative and not restrictive within the spirit of the invention as defined in the appended claims.

I claim: v

1. A new compound corresponding to the general formula wherein X and Y are selected from th group consisting of halogens and amino radicals, A and radical selected from the group consisting "of '-"-SISO3H2, 'PO3H2, Hg'halogen, HgO-acyl, and -SeO3H2 radicals.

2. A new triazine-s'ulphur aryl compound of the formula wherein A and B are selected fro'm'the group consisting of HQOI-I-and halogen, and Me-represents a metallic radical selected from the group con- Hg'Oa=cyl and-SeOzHz. v

3. A new triazine-sulphur-aryl-compound of the formula 4. A new triazine-sulphur-aryl compound of the formula.

N HgO-OO'OHa 5. A new triazine-sulphur-aryl compound of the formula 6. A process for the preparation of a compound of the formula f i a "N l l -Me wherein and Y a'reselected fromthe group consisting of halogens'and amino radicals, A'and Bare selected from the'gro'up consisting'of H, *OH; and halogens, and Me represents a metallic "radical "selected from the group consisting of "-SbOsI-Iz, --PO ;H2, -Hg'halogen, -'-I-IgO-- acyl, and --SeO3H2 radicals, said process'comprising mixing in aqueous reaction medium an "organometallic compound of the formula with an 1,3,5-triazine compoundof the formula "7. A process for the preparation :of aicompound of the :formula N c Me wherein X and Y are selected from the group consisting of halogens and amino-radicals, and

Me represents a metallic radical selected from the group consisting 'of -SbO3H2, -Hgha1ogen, and -'HgO--acyl radicals saidprocess comprising mixing in aqueous reaction medium a diazobenzene compound of the formula with a compound of the "formula.

reducing the 'nitrogroup of the diazobenzene compound to an amine-group, diazotizing vthe =aminegr0up, and vmixing .the diazotized com- ;p'oundtwithia metal compoundsselected from the group consistingpf 'antimonyisalts-iand mercury salts.

8. A process for the preparation of a compound of the formula HgOOOCHa with mercuric acetate.

- 9. A rocess for the preparation ofza compound -of -the formula ll AB wherein X and Y are selected; from the group consisting ofhalogens and amino-radicals, and A and B are selected fromthe group consisting of H, OH and halogen, saidiprocess comprising with a, compound corresponding to the formula JI-sH ERNST A. H. FRIEDHEIM. 

